Peptide helices are frequent mediators of key protein-protein interactions that regulate important biological processes. However, when peptide helices are taken out of protein context and placed into aqueous solution, they usually adopt random-coil conformations, leading to drastic reduction in biological activity and thus diminished therapeutic potential. Side chain crosslinking (“peptide stapling”) is one of the numerous strategies that aim to stabilize and/or mimic peptide helices. Because peptide stapling necessitates macrocyclization, an entropically unfavorable process, very few reactions are known to date that give rise to reasonable yields without undesirable side reactions. Such reactions include intramolecular disulfide bond formation, lactam formation and ruthenium-catalyzed ring-closing metathesis (RCM).
Since protein-embedded peptide α-helices are key structural elements that regulate signaling pathways in cancer, HIV, and other diseases, stapled peptide α-helices have potential in therapeutic applications. Based on the foregoing, there is an ongoing, unmet need for the development of stapled peptides.